Flexibility, Conformation Spaces, and Bioactivity

Conformation constraints and molecular flexibility strongly affect the bioactivity of flexible molecules. The present study offers a new conceptual framework, as well as a practical quantitative procedure, for discussing and quantifying these effects. The theory is formulated in terms of weighted overlaps between the volume in conformation space occupied by the flexible ligand and the pre-prescribed conformational requirements imposed by the host molecule (“region of bioactivity”). From this theory a quantitative structure activity relationship (QSAR) type descriptor, which quantifies the effect of conformation constraints on bioactivity, was derived and the resulting model was shown to be in excellent correlation with the observed activity of the molecules. Three characteristic scenarios for the relationship between flexibility and bioactivity are outlined and demonstrated in realistic systems:  conformationally constrained alanine hexapeptides, a series of substance P analogues, and a set of conformatio...